Interview with Brian G M Durie, MD

When did you first start using the Freelite test for myeloma patients in your clinical practice?

I first became an advocate for the use of Freelite test in the subset of patients with nonsecretory or hyposecretory multiple myeloma. It was simple and relatively inexpensive blood test that allowed identification of the majority of the patients with "nonsecretory myeloma". My personal findings support published data that 70 - 80% of those patients have measurable levels of Freelite and hence measurable disease in the trial setting. Carrying that concept forward, myself and Vincent Rajkumar at the Mayo Clinic, have worked to integrate the Freelite measurements and ratio into the New International Response Criteria for myeloma. (See Leukemia 2006:9, 1467 - 1473)

Will you share with us the evolution of stringent response criteria and validation of stringent response criteria with reference to Freelite?

Well, yes. We advocate the introduction of a quantitative technique for assessing response with Freelite in the stringent complete response (sCR) group. A normal Freelite ratio is known to be a good prognostic factor and predicts for longer remission and survival. Identifying patients with a normal Freelite ratio and sCR is anticipated to be an added benefit in clinical trial evaluations.

To observe stringent complete response would physicians have to order the Freelite test on almost every patient?

Yes, that is right. What has been amazing is that as I started to get the Freelite testing on all of my patients I Realized that it is remarkably helpful, both for assessing response as we as in some of the other categories of potential utility such as early diagnosis, and evaluation of prognosis.

Dr. Durie, since you championed the incorporation of Freelite into sCR, you must believe it is extremely reliable and widely available for the patients.

Right. It is a simple, cheap blood test. Compared to gene expression profiling (GEP) and cytogenetics or FISH analysis, it is more accessible to the practicing clinician. Through my early work with serum beta-2-microglobulin as a prognostic factor, I recognized the particular value of a simple blood test. The use of Freelite can hopefully live up to its potential.

Dr. Barlogie's recent paper in Blood (2007, 110; 827 - 832), identified a subset of poor prognosis patients with Freelite measurements. Is the information helpful in clinical practice?

Absolutely. The opposite is also true where if you don't see a rapid reduction in the Freelite [measurements], that could be the basis for protocol changes. By genes expression profiling (GEP), 13% of patients have a high risk [for] myeloma and perhaps without doing GEP we could identify that 13% subset much more cheaply and simply with baseline and/or serial Freelite measurements.

Do you use SPEP, IFE and Freelite in your practice for up front screening and diagnosis?

Freelite is ordered routinely at baseline for all the patients along with SPEP and IFE. Since I see a lot of referral patients, Freelite is very helpful at baseline and for monitoring such a group of patients.

If you are monitoring patients on therapy, how frequently do you test with Freelite and other assays? Do you monitor them frequently once they're included in a clinical trial? How do you set that up?

Within a trial we do Freelite testing with each cycle of therapy. Aptium Oncology has a frontline trial with Velcade, Cytoxan and dexamethasone with a three week cycle, total six cycles, three weeks apart. With each cycle we take Freelite measurements as part of the protocol. Also, several nonsecretory patients can be evaluated within the trial because we have the Freelite provision.

Do you see a correlation between Freelite measurements and PET scanning?

We have serial PET and ST PET data from which we can show the correlation with Freelite levels. I already know that changes in the Freelite are just as sensitive, maybe even more sensitive versus changes in PET imaging.

Do patients find the International Myeloma Foundation brochure entitled "Understanding Serum Free Light Chain Assays" useful?

Very much so. IMF has worked very hard raising awareness among the patients. Patients are quite well informed about the Freelite assays, perhaps more so than the doctors. They understand the implications from seeing the numbers for themselves.

Do the physicians or patients struggle with fluctuations in serum free light chain (sFLC) measurements or ratios?

I think it is very important to understand that some fluctuations in numbers will occur. We emphasized in the response criteria the normalization of the ratio. If a patient is in a stringent CR, the ratio is normal; however, a relatively minor change can result in an abnormal ratio. The immediate concern of the patient is that they have relapsed. It is important to review and discuss reasons for minor changes such as infection, changes in renal function and /or changes in medications. For patients with light chain disease, minor fluctuations do occur and do not necessarily mean that relapse has occurred. Conversely, minor changes can be real and very important for patients with hyposecretory disease. Further testing may be required to clarify the situation.

Do you screen your MGUS patients with Freelite?

Yes.

Do you use the risk stratification model for your MGUS patients? (Blood 2005, 106 (3); 812 - 817)

Yes. When I'm seeing patients with MGUS or smoldering myeloma, I automatically look at whether it's IgG and if the Freelite ratio is normal to determine if the patient may have very low risk disease. So I certainly use that low cut off.

How frequently would you follow up?

I would automatically set up a more delayed follow up even if I was seeing the patient for the first time. Conversely, if the M-component is > 1.5g/dL and it is not IgG and the Freelite ratio is abnormal, I will see the patient back more frequently until I establish the pattern of disease.

Dr. Durie, what is your perspective on replacing 24 hour urine-based assays with sFLC assays?

I think that is a pretty good idea. It is very, very unlikely that you will miss Bence Jones proteinuria if you use the Freelite test. If you get a Freelite test which is normal, it's extremely unlikely that you have significant Bence Jones proteinuria. That is a very simple answer for me; however, once you get into the nuances of the monitoring over time there are definitely issues related to kidney function that can come along. So one can use the serum Freelite assays for monitoring patients, but you should definitely collect a urine sample every three or four months to check on renal issues.

Given the relatively short half life of free light chains, do you think that the monitoring of FLCs should be routinely used to assess sensitivity of the neoplastic plasma cells to the treatment regimen be changed if a rapid decline in sFLC is not observed?

I think so, but we need more data on that; however, this is potentially a very useful strategy. Some investigators such as Dr. Barlogie are willing to change treatment completely at the end of the first month or cycle; however, most myeloma researchers still assess patients for an "adequate trial" which is two cycles of six weeks [or] eight weeks, unless the patient is really progressing. The situation in which this may be most useful is as part of the screening of new drugs. If the Freelite tests are not going down that's a pretty good signal that the drug is probably not active. I think this can be part of phase 1 - 2 drug screening and may prove to be quite useful in that regard.

Assuming that the sFLC level is proportional to tumor bulk, and given how rapidly the sFLC level changes to reflect a change in the number of neoplastic plasma cells, should the drug dosages and dosage intervals be tailored to each patient to try and maximize tumor kill? For example, if a tumor appears to be highly sensitive to treatment because of a very rapid decline in sFLCs, should one switch to a lower dose to reduce toxicity, and possibly [one that is] administered more frequently to prevent tumor regrowth between dosage intervals?
In the comparison of high dose dexamethasone versus low dose dexamethasone (i.e. the one day per week schedule) it is most likely possible to show the Freelite improvement rapidly with the less toxic, low dose schedule. This is important for the quality of life patients.

The tumor stem cell population in myeloma appears to be comprised of post-germinal center B-lymphocytes. Based on monitoring sFLC levels, if the plasma cell population appears to demonstrate regrowth resistance despite high sensitivity to treatment, and these same plasma have a relatively low proliferative index, should one switch to regimens to which B-lymphocytes are more sensitive? As an example, should one include rituximab (anti-CD20) on the assumption that these patients may have a relatively large proportion of stem cells (B-cells) feeding into the plasma cell population possibly resembling something closer to a lymphoplasmacytic lymphoma?

I think that it's still an open hypothesis. In my opinion, defect is at the plasma cell stage whether it is molecular mechanism or viral susceptibility. Dr Matui's group is looking at it and has shown that the self renewing population is CD 38+ and is sensitive to rituximab; however, in the initial clinical trial using rituximab the length of the remissions was, unfortunately, not prolonged. The question is whether or not myeloma relapse occurs because of regrowth of a residual myeloma cell population or because of recruitment from an early B-cell compartment. Clinical trial data still support the notion that a low level of residual disease gives rise to relapse.